ZA200502032B

ZA200502032B - Organic compounds

Info

Publication number: ZA200502032B
Application number: ZA2005/02032A
Authority: ZA
Inventors: Carolyn Ann Foster; Peter C Hiestand; Paul William Glue
Original assignee: Novartis Ag
Priority date: 2002-09-24
Filing date: 2005-03-10
Publication date: 2005-10-26
Also published as: KR20110038188A; KR101095807B1; US20140271541A1; RU2012153692A; BR0314760A; KR101188943B1; US20120225031A1; AU2003266404B2; CA2499622C; NO20131569L; KR20090125226A; NO20051934L; PL375053A1; CN102526079A; RU2478378C2; TW201100359A; US20090324542A1; NO334908B1; JP4509028B2; KR20050054958A

Description

Organic Compounds

The present invention relates to pharmaceutical combinations comprising at least . one S1P receptor agonist and their uses in treating demyelinating diseases, e.g. multiple sclerosis and disorders associated therewith.

Multiple sclerosis is an immune-mediated disease of the central nervous system white matter with chronic inflammatory demyelination leading to progressive decline of motor and sensory functions and permanent disability. Manifestations of clinical disease usually begin in early adulthood, with women outnumbering men 2:1. The therapy of multiple sclerosis is only partially effective, and in most cases only offers a ' delay in disease progression despite anti-inflammatory and immunosuppressive ) treatment. Clinicians usually categorize patients into four types of disease patterns: « Relapsing-remitting (RR-MS): Discrete motor, sensory, cerebellar or visual attacks that occur over 1-2 weeks and often resolve over 1-2 months, with or without treatment. Some patients accrue disability with each episode, yet remain clinically stable between relapses. About 85% of patients initially experience the

RR form of MS, but within 10 years about half will develop the secondary progressive form. « Secondary-progressive (SP-MS): Initially RR followed by gradually increasing disability, with or without relapses. Major irreversible disabilities appear most often during SP. « Primary-progressive (PP-MS): Progression disease course from onset without any relapses or remissions, affecting about 15% of MS patients. « Progressive-relapsing (PR-MS): Progressive disease from onset with clear acute relapses; periods between relapses characterized by continuing progression.

Accordingly, there is a need for agents which are effective in the treatment of demyelinating diseases, e.g. multiple sclerosis or Guillain-Barré syndrome, e.g. ) including reduction of, alleviation of, stabilization of or relief from the symptoms or illness which affect the organism.

It has now been found that a combination comprising at least one S1P receptor agonist and a co-agent, e.g. as defined below, has a beneficial effect on demyelinating diseases, e.g. multiple sclerosis and the disorders associated therewith.

In accordance with the particular findings of the present invention, there is provided 1. A pharmaceutical combination comprising: a) an S1P receptor agonist, and b) at least one co-agent shown to have clinical activity against at least one demyelinating disease symptom, e.g. a multiple sclerosis symptom or a symptom of

Guillain-Barré syndrome. 2.1 A method for treating a demyelinating disease, e.g. muitiple sclerosis or disorders associated therewith or Guillain-Barré syndrome, comprising co- administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of an S1P receptor agonist, e.g. a compound of formulae | to VII as defined hereinafter, and at least one co-agent, e.g. as indicated hereinafter. 2.2 A method for alleviating or delaying progression of the symptoms of a demyelinating disease, e.g. multiple sclerosis or Guillain-Barré syndrome, comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of an S1P receptor agonist, e.g. a compound of formulae | to VII as defined herein after, and at least one co-agent, e.g. as indicated hereinafter.

An early symptom of multiple sclerosis is optic neuritis. Accordingly, the present invention also provides 2.3 A method for treating, alleviating or delaying progression of optic neuritis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an S1P receptor agonist, e.g. a compound of formulae | to VII as specified herein after, e.g. Compound A or B or a pharmaceutically acceptable salt ' thereof. 3. A pharmaceutical combination as disclosed herein for use in any one of the methods 2.1 to 2.3.

4.1 A pharmaceutical composition for treating, alleviating or delaying progression of . optic neuritis comprising an S1P receptor agonist, e.g. a compound of formulae 1 to

Vil as defined herein after, e.g. Compound A or B, together with one or more . pharmaceutically acceptable diluents or carriers therefor. 4.2 A compound of formulae | to VII as defined herein after, e.g. Compound A or B, for use in the treatment, alleviating or delay of progression of optic neuritis. 4.3 An S1P receptor agonist, e.g. a compound of formulae | to Vil as defined herein after, e.g. Compound A or B, for use in the preparation of a medicament for use in the treatment, alleviating or delay of progression of optic neuritis. 5.1 Use of an S1P receptor agonist, e.g. a compound of formulae | to VII as defined herein after, e.g. Compound A or B, for the preparation of a medicament for treating, alleviating or delaying the progression of optic neuritis. 5.2 Use of a) a sphingosine-1-phosphate (S1P) receptor agonist, and b} at least one co-agent shown to have clinical activity against at least one symptom of a demyelinating disease, for the preparation of a pharmaceutical combination for treating, alleviating or delaying progression of the symptoms of a demyelinating disease, e.g. for the preparation of a pharmaceutical combination for separate, simuitaneous or sequential use in such a method. 5.3 A pharmaceutical composition as disclosed herein for separate, simultaneous or sequential use in medicine, e.g. in a method as disclosed at 2.1 to 2.3.

The term "pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

The term “fixed combination” as that term is used herein means that the active ingredients, e.g. the S1P receptor agonist and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. As an example, a ‘ fixed combination would be one capsule containing two active ingredients.

The term “non-fixed combination” as that term is used herein means that the active ingredients, e.g. the S1P receptor agonist and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body, preferably at the same time. As an . example, a non-fixed combination would be two capsules each containing one active ingredient where the purpose is to have the patient achieve treatment with both active ingredients together in the body.

An S1P receptor agonist is an immunomodulating compound which elicits a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, without evoking a generalized immunosuppression. Naive cells are sequestered; CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's paiches (PP), and thus for example infiltration of cells into transplanted organs is inhibited.

Examples of appropriate S1P receptor agonists are, for example: - Compounds as disclosed in EP627406A1, e.g. a compound of formula

Bil .

R,RN CH,OR,

R, wherein Rj is a straight- or branched (C2.22)carbon chain - which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NRg, wherein Rg is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or - which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or

Riis - a phenylalkyl wherein alkyl is a straight- or branched (Cs.20)carbon chain; or - a phenylalkyl wherein alkyl is a straight- or branched (C;.3p)carbon chain wherein } said phenylalkyl is substituted by - a straight- or branched (Ce.20)carbon chain optionally substituted by halogen, - a straight- or branched (Ce.20)alkoxy chain optionally substitued by halogen,

- a straight- or branched (Ce.20)alkenyloxy, - phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, - cycloalkylalkyl substituted by Ce.20alkyl, . - heteroarylalkyl substituted by Cg 2palkyl, - heterocyclic Cg.p0alkyl or - heterocyclic alkyl substituted by Ca.a0alkyl, and wherein the alkyl moiety may have - in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NRg, wherein Rs is as defined above, and - as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of Ry, Rs, Rs and Rs, independently, is H, Cy.4 alkyl or acyl or a pharmaceutically acceptable salt thereof; - Compounds as disclosed in EP 1002792A1, e.g. a compound of formula ¢ H,OR", q

RNC OH Cc — cra) ~ CH,ORY, i wherein mis 1 to 9 and each of R’, R's, R's and R’s, independently, is H, alkyl or acyl, or a pharmaceutically acceptable salt thereof; - Compounds as disclosed in EP0778263 A1, e.g. a compound of formula ill

N R",R", y

X

(CH,)..OR", m ‘

wherein W is H; Cysalkyl, Ca.salkenyl or Ca-salkynyl; unsubstituted or by OH substituted phenyl; R”,O(CHj),; or Cy.alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, Cs.scycloalkyl, phenyl and phenyl substituted by OH;

X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3 substitutents selected from the group consisting of Cy. alkyl, OH, Cy.salkoxy, acyloxy, amino, C,.alkylamino, acylamino, oxo, haloC,.galkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of Cy.galkyl, OH, Cgalkoxy, acyl, acyloxy, amino, C.salkylamino, acylamino, haloC.salkyl and halogen; Y is H,

Cisalkyl, OH, C,.alkoxy, acyl, acyloxy, amino, C,.ealkylamino, acylamino, haloC;. salkyl or halogen, Z; is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6<p+q<23, mis 1,20r3, nis 2 or 3, each of R”y, R"2, R"3and R"4, independently, is H, Ci.q4alkyl or acyl, or a pharmaceutically acceptable salt thereof, - Compounds as disclosed in W002/1 8395, e.g. a compound of formula {Va or IVb

Hea R,, Hef ra

ING bo (N(CH P =o noo po

STE

(CHMCH, YorRaa IVb wherein X, is O, S, NRys or a group ~(CHa)na-, which group is unsubstituted or . substituted by 1 to 4 halogen; n, is 1 or 2, Rs is H or (Ci.g)alkyl, which alkyl is unsubstituted or substituted by halogen; Ri, is H, OH, (Ci.s)alkyl or O(Ci4)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R, is H, OH or (C1. s)alkyl, wherein alkyl is unsubstituted or substituted by halogen; each Ra, is . independently selected from H or (C.4)alkyl, which alkyl is unsubstituted or substitued by halogen; Ra, is H, OH, halogen or O(C1.4)alkyl wherein alkyl is unsubstituted or substituted by halogen; and Ra, is H, OH, halogen, (Ci.4)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C.s)alkyl wherein alky! is unsubstituted or substituted by halogen; Y, is —-CHy-, -C(O)-, -CH(OH)-, -C(=NOH)- , OorS, and Ra, is (Cs-14)alkyl or (Ca14)alkenyl; or a pharmaceutically acceptable salt or hydrate thereof; - Compounds as disclosed in WO 02/076995, e.g. a compound of formula V

Ric

RL Roct———— (CH,)m,-X Ry,

R. \ wherein me is1,2or3;

X. is O or a direct bond;

Ri is H; Ci.¢ alkyl optionally substituted by OH, acyl, halogen, Cs. ocycloalkyl, phenyl or hydroxy-phenylene; C,.¢alkenyl; Cz ¢alkynyl; or phenyl optionally substituted by OH;

Ro: is

OR,

To 0 om, lo} wherein Rs. is H or Cy4alkyl optionally substituted by 1, 2 or 3 halogen atoms, and Rg is H or Cy4alkyl optionally substituted by halogen; each of Rs; and Ra, independently, is H, Cy.4alkyl optionally substituted by halogen, or acyl, and

Rc. is Cya.20alkyl which may optionally have in the chain an oxygen atom and which ) may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

. Bye (a) . Rye wherein Ry. is H, Cq.4alkyl or Cy.4alkoxy, and Rg. is substituted C.zpalkanoyl, phenylCi.14alkyl wherein the Cy.j4alkyl is optionally substituted by halogen or

OH, cycloalkylCy.15alkoxy or phenylCj.14alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, Ci.4alkyl and/or C;.salkoxy, phenylC. 1salkoxy-

Ci.1aalkyl, phenoxyCi.i4alkoxy or phenoxyCi.1aalkyl,

Rc being also a residue of formula (a) wherein Rg. is Ci.14alkoxy when Ric is Ci. aalkyl,

Ca.salkenyl or C,.salkynyl, or a compound of formula Vi

R,, RBs.

Ry RN Tr enn—C

CH,-OR,, Rex vi wherein nx is2,3o0ré4

Rix is H; Cygalkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; Ca..salkenyl; Ca.salkynyl; or phenyl optionally substituted by

OH;

Rax is H, C4 alkyl or acyl each of Ra, and Ry, independently is H, Cy4alkyl optionally substituted by halogen or . acyl,

Rsx is H, Cq4alkyl or Cq.4alkoxy, and . Rex is Cy.20 alkanoyl substituted by cycloalkyl; cyloalkylCi.14alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, Cy.salkyl and/or C4.salkoxy;

phenylC1.14alkoxy wherein the phenyl ring is optionally substituted by halogen,

Ci.4alkyl and/or Cy4alkoxy,

Rex being also C,4.i4alkoxy when Ry, is C,.salkyl substituted by OH, or pentyloxy or } hexyloxy when Ri, is C14akyl, provided that Re, is other than phenyl-butylenoxy when either Rs, is H or Ry, is methyl, or a pharmaceutically acceptable salt thereof; - Compounds as disclosed in WO02/06268Al, e.g. a compound of formula VII

NR, ,R,, Res Pia

Safed Snr,

R340 S vil wherein each of Ryq and Raq, independently, is H or an amino-protecting group;

Rag is hydrogen or a hydroxy-protecting group;

Raq is lower alkyl;

Ng is an integer of 1 to 6;

Xq is ethylene, vinylene, ethynylene, a group having a formula — D-CH,- (wherein D is carbonyl, — CH(OH)-, O, S or N), aryl or aryl substituted by up to three substitutents selected from group a as defined hereinafter;

Yq is single bond, Ci.iealkylene, Ci.i0alkylene which is substituted by up to three substitutents selected from groups a and b, Cy.1palkylene having O or S in the middie or end of the carbon chain, or Cy_jpalkylene having O or S in the middle or end of the carbon chain which is substituted by up to three substituents selected from groups a and b; :

Rsa is hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl substituted by up to three substituents selected from groups a and b, aryl substituted by up to three substituents selected from groups a and b, or heterocycle substituted by up to three substituents selected from groups a and b; and } each of Req and Ryq, independently, is H or a substituent selected from group a;

<group a > is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, lower alkyithio, . carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-lower alkylamino, di-lower alkylamino, lower aliphatic acylamino, cyano or nitro; <group b > is cycloalkyl, aryl, heterocycle, each being optionally substituted by up to three substituents selected from group a; with the proviso that when Rs is hydrogen, Yq is a either a single bond or linear Ci.10 alkylene, or a pharmacologically acceptable salt or ester thereof. -Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a compound of formula VI:

NR, Roe Ree XY Re iota ST

S

R,,0 Rae vill wherein Rye,Rze,R3e,R4e,Rse,Rse,R7e, Ne, Xe and Y, are as disclosed in JP-14316985; or a pharmacologically acceptable salt or ester thereof. -Compounds as disclosed in WO 03/29184 and WO 03/29205, e.g. compounds of formula 1X

Ry X, Ra NH,

Avg TL _—cn,on IX

R, (CH) CH,OH wherein X;is O or S, and Ry, Ry, Rar and ny are as disclosed in WO 03/29184 and 03/29205, e.g. 2-amino-z-1-4-(3-benzyloxyphenoxy)-2-chlorophenylipropyl-1,3- propane-diol or 2-amino-2-[4-(benzyloxyphenylthio)-2- chlorophenyl]propyi-1,3- propane-diol.

In each case where citations of patent applications are given, the subject matter "relating to the compounds is hereby incorporated into the present application by reference.

Acyl may be a residue R,-CO- wherein Ry is Cq.alkyl, Cs.scycloalkyl, phenyl or phenyl-C,.salkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

When in the compounds of formula | the carbon chain as R; is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.

Preferred compounds of formula | are those wherein Ry is Cy3.20alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R; is phenylalkyl substituted by Ce.14-alkyl chain optionally substituted by halogen and the alkyl moiety is a Cy.¢alkyl optionally substituted by hydroxy. More preferably, R, is phenyl-C, alkyl substituted on the phenyl by a straight or branched, preferably straight, Cg.14alkyl chain. The Cg.14alkyl chain may be in ortho, meta or para, preferably in para.

Preferably each of R, to Rs is H.

A preferred compound of formula | is 2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred S1P receptor agonist of formula | is FTY720, i.e. 2-amino-2-[2- (4-octylphenyl) ethyl}propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:

HO H

Hoy HCI

A preferred compound of formula ll is the one wherein each of R'; to R'sisHand m is 4, i.e. 2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl}ethyl}propane-1,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as

Compound B), e.g the hydrochloride. . A preferred compound of formula li is the one wherein W is CH3, each of R”y to R”; is H, Z» is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2- . methyl-butanol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride. The R-enantiomer is particularly preferred.

A preferred compound of formula IVa is the FTY720-phosphate (R,, is H, Ra, is OH,

Xa is O, Ria and Ryp are OH). A preferred compound of formula [Vb is the Compound

C-phosphate (Rza is H, Rap, is OH, X, is O, Ry; and Ryp are OH, Y, is O and Ry, is heptyl). A preferred compound of formula V is Compound B-phosphate.

A preferred compound of formula V is phosphoric acid mono-[(R)-2-amino-2-methyl- 4-(4-pentyloxy-phenyl)-butyl]ester.

A preferred compound of formula Vill is (2R)-2-amino-4-[3-(4- cyclohexyloxybutyl)benzo[b]thien-6-yl}-2-methylbutan-1-ol.

When the compounds of formulae 1 to IX have one or more asymmetric centers in the molecule, the present invention is to be understood as embracing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof are embraced. Compounds of formula lll or IVb, when the carbon atom bearing the amino group is asymmetric, have preferably the R-configuration at this carbon atom.

Examples of pharmaceutically acceptable salts of the compounds of the formulae 1 to

IX include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. The compounds and salts of the methods of the present invention encompass hydrate and solvate forms.

The co-agent b) may be selected from the following groups of compounds: i) Interferons, e.g. pegylated or non-pegylated a-interferons, or -interferons or t-interferons, e.g. administered by subcutaneous, intramuscular or oral routes, preferably B-interferons; . ii) An altered peptide ligand such as Glatiramer, e.g. in the acetate form;

li) Immunosuppressants with optionally antiproliferative/antineoplastic activity, e.g. mitoxantrone, methotrexate, azathioprine, cyclophosphamide, or steroids, e.g. methylprednisolone, prednisone or dexamethasone, or steroid-secreting agents, e.g. ACTH; iv) Adenosine deaminase inhibitors, e.g. cladribine; v) IV immunoglobulin G (e.g. as disclosed in Neurology, 1998, May 50(5):1273-81 vi) Monoclonal antibodies to various T-cell surface markers, e.g. natalizumab (ANTEGREN®) or alemtuzumab; vii) TH2 promoting cytokines, e.g. IL-4, IL-10, or compounds which inhibit expression of TH1 promoting cytokines, e.g. phosphodiesterase inhibitors, e.g. pentoxifyliine; viii) Antispasticity agents including baclofen, diazepam, piracetam, dantrolene, lamotrigine, rifluzole, tizanidine, clonidine, beta blockers, cyproheptadine, orphenadrine or cannabinoids; ix) AMPA glutamate receptor antagonists, e.g. 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo(f)quinoxaline, [1,2,3,4,-tetrahydro-7-morpholin-yl-2,3-dioxo-6- (trifluoromethyl)quinoxalin-1-yljmethylphosphonate, 1-(4-aminophenyl)-4- methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine, or (-)1-(4-aminophenyl)-4- methyl-7,8-methylene-dioxy-4,5-dihydro-3-methylcarbamoyl-2,3- benzodiazepine; x) Inhibitors of VCAM-1 expression or antagonists of its ligand, e.g. antagonists of the 41 integrin VLA-4 and/or alpha-4-beta-7 integrins, e.g. natalizumab (ANTEGREN®); xi) Anti-Macrophage migration inhibitory factor (Anti-MIF); xii) Cathepsin S inhibitors; xiii) mTor inhibitors.

Cathepsin S inhibitors include e.g.: a) a compound as disclosed in WO 03/20721, e.g. a compound of formula:

Claims

Case 4-32544A CLAIMS

1. Apharmaceutical combination comprising: a) a sphingosine-1-phosphate (S1P) receptor agonist, and b) at least one co-agent shown to have clinical activity against at least one symptom of a demyelinating disease.

2. A pharmaceutical composition for treating, alleviating or delaying progression of optic neuritis comprising an S1P receptor agonist together with one or more pharmaceutically acceptable diluents or carriers therefor.

3. A combination or composition according to claim 1 or claim 2 wherein the S1P receptor agonist is selected from the compounds of formulae | to lll, IVa, IVb, and V to VII substantially as described and defined herein.

4. A combination according to claim 1 or claim 3, wherein the co-agent b) is selected from the group consisting of interferons, altered peptide ligands, immunosuppressants, adenosine deaminase inhibitors, IV immunoglobulin G, monoclonal antibodies to T-cell surface markers, TH2 promoting cytokines, compounds which inhibit expression of TH1 promoting cytokines, antispasticity agents, AMPA glutamate receptor antagonists, inhibitors of VCAM-1 expression or antagonists of its ligand, anti-macrophage migration inhibitory factor, cathepsin S inhibitors and mTOR inhibitors.

5. A combination or composition according to any preceding claim, wherein the S1P receptor agonist is selected from 2-amino-2-[2-(4-octylphenyl) ethyl]propane- 1,3-diol, 2-amino-2-{2-[4-(1-ox0-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol and their respective phosphate, in free form or in a pharmaceutically acceptable salt form.

6. Use of a) an S1P receptor agonist, and b) at least one co-agent shown to have clinical activity against at least one symptom of a demyelinating disease, in the manufacture of a medicament or medicaments for treating, alleviating or delaying progression of the symptoms of a demyelinating disease by co-administration thereof. AmcNDED SHEET

7. Use of an S1P receptor agonist in the manufacture of a medicament for treating, alleviating or delaying progression of optic neuritis.

8. Use according to claim 6 or 7 wherein the S1P receptor agonist is selected from a compound of formulae | to IX substantially as described and defined herein.

9. Use according to claim 6, 7 or 8 wherein the S1P receptor agonist is selected from 2-amino-2-[2-(4-octylphenyl)ethyl}propane-1,3-diol, 2-amino-2-{2-[4- (1-ox0-5-phenylpentyl)phenyilethyl}propane-1,3-diol and their respective phosphate, in free form or in a pharmaceutically acceptable salt form.

10. Use according to claim 6, wherein the co-agent b) is selected from the group consisting of interferons, altered peptide ligands, immunosuppressants, adenosine deaminase inhibitors, IV immunoglobulin G, monoclonal antibodies to T-cell surface markers, TH2 promoting cytokines, compounds which inhibit expression of TH1 promoting cytokines, antispasticity agents, AMPA glutamate receptor antagonists, inhibitors of VCAM-1 expression or antagonists of its ligand, anti-macrophage migration inhibitory factor, cathepsin S inhibitors and mTOR inhibitors.

11. A combination or composition according to any of claims 1 to 5, for treating, alleviating or delaying progression of the symptoms of a demyelinating disease.

12. Use of a compound of formula VIII or IX for the preparation of a medicament for treating, alleviating or delaying progression of multiple sclerosis.

13. Use of a compound of formula IX for the preparation of a medicament for treating, alleviating or delaying progression of multiple sclerosis.

14. Use of a compound of formula VIII or IX for the preparation of a medicament for treating, alleviating or delaying progression of optic neuritis.

15. Use of a compound of formula IX for the preparation of a medicament for treating, alleviating or delaying progression of optic neuritis. AMENDED SHEET

-28A-

16. A pharmaceutical combination according to claim 1, substantially as herein described and exemplified.

17. Use according to any one of claims 6, 7 12, 13, 14 or 15, substantially as herein described and exemplified. AMENDED SHEET